IFN-GAMMA INHIBITS THE REPLICATION OF LISTERIA-MONOCYTOGENES IN HEPATOCYTES

We previously reported that the bulk of Listeria monocytogenes injecte d intravenously into mice is taken up in the liver and replicates with in the parenchymal cells (hepatocytes). Although IFN-gamma is known to play an important role in host defenses to listerial infections of th e liver, the mechanism(s) that underlies this role remains to be fully ' delineated. In the initial experiments presented here, we demonstrat ed the elevated expression of IFN-gamma message in the livers of mice during primary listerial infections. Subsequent experiments showed tha t the listerial burden of the hepatocyte population was increased sign ificantly in mice administered monoclonal anti-IFN-gamma. Conversely, the administration of murine rIFN-gamma resulted in a marked (2 log10) decrease in the number of hepatocyte-associated Listeria. In vitro, I FN-gamma stimulated the listericidal activity of purified hepatocytes. Infected hepatocytes incubated in the presence of > 0.1 U/ml murine r IFN-gamma exhibited a significant reduction in intracellular Listeria. The elevated antilisterial activity of IFN-gamma-treated hepatocytes in culture was abrogated by the presence of compounds that scavenged o r inhibited the production of reactive oxygen intermediates. Taken tog ether, these findings suggest that activation of the oxygen-dependent, antimicrobial activity of hepatocytes may constitute a principal effe ctor function of IFN-gamma in host defenses to listerial infections of the liver.